tbuckley/cabot-search huggingface dataset:
Abstract 620: Regulation of anti-tumor immune response by EphA2 receptor tyrosine kinase
Authors: Roger Xiaojun Shi, Ryan Lingerak, So-Yeon Kim, Wei Wang, Khalid Sossey-Alaoui, Bingcheng Wang
Journal: Cancer Research (2023)

Abstract Eph receptors are the largest family of receptor tyrosine kinases. Overexpression of EphA2 is common across many types of human cancer, particularly in the late stage malignant diseases. We report here that EphA2 knock-out causes delayed tumor growth in several syngeneic mouse caner models, such as breast, colon, lung, and prostate cancer as well as melanoma. However, such effects are missing in immune deficient mice, which suggests the involvement of immune components. Immunophenotyping of the tumors shows elevated T cell infiltration and accompanied by reduced MDSC population in the EphA2 KO tumors. Single cell transcriptomic analysis and cytokine measurements support these results showing increased production of CCL5, CXCL9 and IFNg in the EphA2 KO tumors. Analysis on tumors at very early time points reveals elevated levels of CXCL1 and CXCL2 which recruits suppressive MDSCs. Consistently, larger population of MDSCs was found in PBMCs from the control tumor bearing mice than those bearing EphA2 KO tumors. These results suggest that EphA2 in cancer cells drive the production of CXCL1 and CXCL2 to recruit suppressive MDSCs to the tumor site, thus subvert the host anti-tumor immune surveillance. Targeting the overexpressed EphA2 in cancer can help reshape the tumor micro- environment towards type I anti-tumor immune response. Citation Format: Roger Xiaojun Shi, Ryan Lingerak, So-Yeon Kim, Wei Wang, Khalid Sossey-Alaoui, Bingcheng Wang. Regulation of anti-tumor immune response by EphA2 receptor tyrosine kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 620.
Abstract 611: Sex disparities in cancer immunoediting
Authors: Katey Hunt, Elise Alspach
Journal: Cancer Research (2023)

Abstract Cancer immunoediting is the process through which tumor specific T cell populations both prevent cancer development and apply selective pressure for the outgrowth of less immunogenic tumors with reduced neoantigen burden. Male and female immune systems demonstrate distinct differences that drive characterized disparities in response to viral infection and immunization. While several recent publications have shown that anti-tumor immune responses are inhibited by male sex hormone signaling, a critical gap in knowledge exists surrounding sex-based differences in the larger-scale process of immunoediting. Because the residual neoantigen burden expressed after tumor escape from immune surveillance is an important determinant of rejection following immune checkpoint blockade, disparities in immunoediting between males and females could have profound impacts on both cancer incidence and response to therapy. The purpose of our studies is to determine if the enhanced functionality of female T cells results in more effective immunoediting of tumors that evolve in females versus those that evolve in males. We have used the 3-methylcholanthrene carcinogen-induced tumor model and several transplant tumor models to determine if T cell function regulates differential cancer development between the sexes. We have also analyzed predicted neoantigen burden in male and female patients with melanoma and lung cancer to identify sex-based differences in tumor immunogenicity. We have found that female T cell responses are more effective at preventing tumor occurrence and delaying tumor outgrowth compared to male T cell responses in mice, which may help to explain established sex-based disparities in cancer incidence in the human population. In comparison, male patient tumors were more likely to express high neoantigen burden compared to their female counterparts. These results suggest that while stronger anti-tumor T cell responses in females are helpful in driving lower cancer incidence in females compared to males, this disparity may also result the development of tumors that express greater numbers of immunogenic neoantigens in males versus females. A better understanding of how sex impacts the entire process of immunoediting will help to explain cancer disparities between the sexes and identify potential new therapeutic strategies that can benefit all patients. Citation Format: Katey Hunt, Elise Alspach. Sex disparities in cancer immunoediting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 611.
Abstract 6189: Targeting DNA damage responsive pathways in cancer therapy
Authors: Junjie Chen
Journal: Cancer Research (2023)

Abstract DNA double strand breaks (DSBs) result in activation of several key DNA damage response (DDR) kinases including ATM, ATR, and DNA-PK. These protein kinases not only promote DNA damage-induced checkpoint control, but also facilitate DSB repair in humans. Thus, these DDR kinases have become promising drug targets for cancer therapy. However, the benefits of targeting DDR kinases remain to be realized, in part due to the lack of predictive biomarkers. By undertaking CRISPR screens with inhibitors targeting key DDR kinases, we obtained a global and unbiased view of genetic interactions with DDR inhibition. Additionally, we compared the synergistic effects of combining different DDR inhibitors and found that an ATM inhibitor plus a PARP inhibitor induced dramatic levels of cell death, probably through promoting apoptosis. Our results provide a better understanding of DDR pathways, which may facilitate the use of these DDR-targeting agents in cancer therapy. Moreover, To provide comprehensive and unbiased perspective of DDR signaling pathways, we performed 30 fluorescence-activated cell sorting-based genome-wide CRISPR screens with antibodies recognizing distinct endogenous DNA damage-signaling proteins to identify new regulators involved in DNA damage response (DDR). We discovered that proteasome-mediated processing is an early and prerequisite event for cells to trigger camptothecin- and etoposide-induced DDR signaling. Furthermore, we identified PRMT1 and PRMT5 as new modulators that regulate ATM protein level. Moreover, we discovered that GNB1L is a master regulator of DDR signaling via its role as a co-chaperone for PIKK proteins. Collectively, these screens offer a rich resource for further investigation of DDR, which may provide insight into strategies of targeting these DDR pathways to improve therapeutic outcomes. Citation Format: Junjie Chen. Targeting DNA damage responsive pathways in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6189.
Abstract 6192: MSI2 regulates DNA damage response signaling and tumor progression in murine NSCLC
Authors: Igor Bychkov, Alexander Deneka, Iuliia Topchu, Rajendra P. Pangeni, Christopher Lengner, Evgeny Izumchenko, Jyoti Patel, John Karanicolas, Petr Makhov, Yanis Boumber
Journal: Cancer Research (2023)

Abstract Lung cancer is one of the most frequently diagnosed cancers and is the leading cause of cancer-related death worldwide, accounting for &amp;gt;2.2 million of new cancer diagnoses and 1.8 million cancer-related deaths in 2020. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, including adenocarcinomas and squamous cell carcinomas. Many lung adenocarcinomas have activating driver mutations in KRAS (~32% tumors), often co-occurring with mutations inactivating the TP53 tumor suppressor. Expression of the RNA-binding protein Musashi-2 (MSI2) MSI2 regulates target mRNA translation, and its expression is progressively elevated along with tumor stage in lung cancers. We previously showed that MSI2 actively promotes lung cancer growth, invasion, and metastasis, in part through promoting expression and activity of the TGFβR1/SMAD3 and EGFR signaling cascades. We now find that genetic MSI2 deficiency in a murine lung tumor model, Krasmut/Trp53KO/Msi2KO (KPM2) decreases both the total tumor number and tumor burden in comparison to control Krasmut/Trp53KO (KP) mice. Using a panel of KPM2 and KP cell lines we established from tumors from these mice, we found KPM2 cell lines demonstrate a significant decrease in proliferation compared to KP cell lines. Interestingly, reverse phase protein array (RPPA) comparison analysis of KPM2 and KP cell lines showed that MSI2 strongly and positively regulates expression of Ataxia-Telangiectasia Mutated (ATM) protein, with lower levels observed in KPM2 cells. The ATM serine/threonine protein kinase is a key transducer of DDR signaling in cases of double-strand breaks; ATM activation causes G1/S cell cycle arrest, contributes to efficiency of DNA repair, and triggers apoptosis in cases of repair failure. Notably, KPM2 cells showed significantly higher levels of γH2AX, suggesting inefficient DDR. Finally, untreated or cisplatin-treated KPM2 cells demonstrated G2/M arrest and had increased level of apoptosis as demonstrated by increase in caspase 3 cleavage, consistent with ATM loss and compensatory activation of Ataxia-telangiectasia and Rad3-related protein (ATR). Taken together, our data suggests that one of the consequences of MSI2 upregulation in NSCLC includes maintenance of an efficient DDR. Targeting MSI2 and its downstream signaling would be of therapeutic interest. Citation Format: Igor Bychkov, Alexander Deneka, Iuliia Topchu, Rajendra P. Pangeni, Christopher Lengner, Evgeny Izumchenko, Jyoti Patel, John Karanicolas, Petr Makhov, Yanis Boumber. MSI2 regulates DNA damage response signaling and tumor progression in murine NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6192.
Abstract 3933: RRM2 inhibition by COH29 is a potential therapeutic strategy for atypical teratoid rhabdoid tumors
Authors: Le Hien Giang, Tai-Tong Wong, Che-Chang Chang
Journal: Cancer Research (2023)

Abstract Introduction: Atypical teratoid rhabdoid tumors (ATRT) are a rare but aggressive malignancy in central nervous system, commonly occurring in early childhood. ATRT patients face a dismal prognosis despite aggressive therapy. Development of both effective and protective targeted therapy is an emerging necessity. It has been reported that RRM2 is a master driver of aggressiveness and a poor prognosis biomarker in several cancers. However, little is known about RRM2 function in ATRT. The aim of this study is to assess the roles of RRM2 in ATRT and elucidate the therapeutic potential of RRM2 to cure the ATRT. Methods: Expression of RRM2 was evaluated by molecular profiling analysis and was confirmed by IHC in both ATRT patients and PDX tissues. Follow-up in vitro studies used 3 different cell lines to elucidate the oncogenic role of RRM2 in ATRT cells. The efficacy of COH29, an RRM2 inhibitor, was assessed in vitro. ATRT model of SCID mice orthotopically injected with ATRT cells were used to test the efficiency of COH29 for in vivo. Western blot and RNA-sequencing were used to determine the mechanisms of RRM2 transcriptional activation in ATRT. Results: Molecular profiling results revealed that RRM2 was relatively highly expressed in ATRT tissues and cell lines. Clinical relevance analysis results showed that the RRM2 expression level was associated with poor prognosis among ATRT patients. Knockdown of RRM2 by shRNAs significantly reduced ATRT cells colonies formation, proliferation and migration. A similar but more pronounced inhibitory effect was observed when COH29 was used to target RMM2. Inhibition of RRM2 by shRNAs or COH29 significantly induced cell death via DNA damage and/or apoptosis pathways. In vivo results demonstrated that COH29 could suppressed ATRT tumor growth and extend mice overall survival. Conclusion: Our study identified RRM2 as a potential mediator of oncogenic cellular functions in ATRT cell lines. We propose that highly expressed RRM2 is associated with poor patient outcomes, and inhibition of RRM2 by COH29 may present a significant therapeutic value in ATRT. Citation Format: Le Hien Giang, Tai-Tong Wong, Che-Chang Chang. RRM2 inhibition by COH29 is a potential therapeutic strategy for atypical teratoid rhabdoid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3933.
Abstract 5044: Antitumor activity comparison of two somatostatin receptor ligands radiolabeled with Lutetium-177 (SSO110 and DOTA-TATE) alone or combined with chemotherapy in mice bearing AR42J SST2-positive tumors
Authors: Olivier Raguin, Marcel Krüger, Peggy Provent, Funda Cay, Elodie Marie dit chatel, Marie Lux, Stéphane Lezmi, Florence Meyer-Losic, Pascale Plas, Ben Pais, Cyril Berthet
Journal: Cancer Research (2023)

Abstract Only a limited number of studies have compared the therapeutic effects of repetitive cycles of radiolabeled somatostatin (SST) analogues or assessed potential synergy of these analogues with chemotherapy agents. Hence, a comparison was conducted in an in vivo AR42J tumor model with an SST2 antagonist, [177Lu]Lu-satoreotide tetraxetan ([177Lu]LuSSO110), and a SST2 agonist, [177Lu]Lu-DOTA-TATE. The efficacy of treatment combining [177Lu]Lu-satoreotide tetraxetan with capecitabine plus temozolomide was also assessed. Swiss Nude mice were xenografted with AR42J tumor cells. For the evaluation of the tumor response to radiation therapy, animals received one weekly dose of [177Lu]LuSSO110 or [177Lu]Lu-DOTA-TATE for four consecutive weeks. For combined treatments, animals received one weekly dose of [177Lu]LuSSO110 at 20 MBq for four consecutive weeks in association with daily doses of capecitabine and temozolomide (CAPTEM). Weekly treatment for four consecutive weeks with [177Lu]LuSSO110 at 15 MBq revealed a significantly reduced tumor growth, with 68 days to reach a tumor volume of 850 mm3, compared to [177Lu]Lu-DOTA-TATE at 15 MBq or 30 MBq, with, respectively, 43 days and 48 days. This was associated with a 3.5 fold higher tumor uptake of [177Lu]LuSSO110 (15 MBq) compared to [177Lu]Lu-DOTA-TATE, with no or mild effects on body weight, hematological toxicity, or renal toxicity. In AR42J tumor-bearing mice treated once a week for four consecutive weeks, [177Lu]LuSSO110 (15 MBq) associated with CAPTEM regimen did not significantly increase the median time to reach a tumor volume of 1000 mm3 as compared to treatment with [177Lu]Lu-satoreotide alone: 50.7 vs 42.2 days, respectively. The association of the two treatments only led to mild weight losses. Repeated administrations of [177Lu]LuSSO110 were able to potentiate peptide receptor radionuclide therapy with a higher tumor uptake and longer median survival compared to [177Lu]Lu-DOTA-TATE. The The combination of [177Lu]Lu-satoreotide with capecitabine and temozolomide did not show any synergy, but no antagonism was observed either. Citation Format: Olivier Raguin, Marcel Krüger, Peggy Provent, Funda Cay, Elodie Marie dit chatel, Marie Lux, Stéphane Lezmi, Florence Meyer-Losic, Pascale Plas, Ben Pais, Cyril Berthet. Antitumor activity comparison of two somatostatin receptor ligands radiolabeled with Lutetium-177 (SSO110 and DOTA-TATE) alone or combined with chemotherapy in mice bearing AR42J SST2-positive tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5044.
Abstract 3828: Herbal extracts from lycii radicis corex and achyranthes japonica prevent multiple myeloma progression
Authors: Syed Hassan Mehdi, Sun-OK Lee, Dam Huh, Donghoon Yoon
Journal: Cancer Research (2023)

Abstract Multiple Myeloma (MM) is a plasma cell malignancy that, despite advances in treatment, remains incurable. In over 90% of MM patients, aberrant bone remodeling occurs and results in osteolytic lesions. Korean traditional medicine has a long-standing interest in healthy foods to enhance the immune system, energy-boost, and Yin-and-Yang balance. Traditional medicine has used herbal extracts (HE) from natural plants with fewer side effects and long-term treatment tolerance. In earlier studies, lycii radices cortex (LRC) and achyranthes japonica (AJ) containing HE have demonstrated the ability to enhance cell growth and mineralization of osteoblast cells while also inhibiting osteoclast differentiation. The current study investigated the effects of LRC+AJ containing HE on murine 5TGM1 MM-bearing mice.This HE significantly increased the mouse survivals of both Treatment before Transplant (TbT) and Treatment after Transplant (TaT) groups with median survivals of undetermined and 52.5 days, respectively, while MM control had a median survival of 42 days. The Mantel-Cox test found that TbT and TaT mice were significantly different from the control group (P=0.0014 and 0.0182, respectively). In histomorphometric analysis, the spines were scanned by micro-CT and revealed that TbT and TaT groups had significantly increased bone volume over total volume (BV/TV) than control. To see if HE affects cell growth of myeloma cells and osteoblast cells, we further investigated the HE on preosteoblast cell line MC3T3-E1, mouse MM cell line 5TGM1-Luc, and human MM cell line U-266. Cells were treated with HE, and viability was assessed at 48 and 96 hours post-treatment. Remarkably, LRC+AJ containing HE increased MC3T3-E1 cell growth while it decreased 5TGM1 and U-266 cell viability. In addition, we found the DAP3G in HE used in this study.Our results demonstrated that LRC+AJ HE prevents MM and promotes bone formation in 5TGM1 engrafted NSG mice. We also found that LRC+AJ HE suppresses myeloma cell growth and enhances osteoblast cell survival. Although it is yet to be defined, a correlation of osteoblast activity and myeloma cell inhibition suggests a possible connection of these events to prevent MM progression. Citation Format: Syed Hassan Mehdi, Sun-OK Lee, Dam Huh, Donghoon Yoon. Herbal extracts from lycii radicis corex and achyranthes japonica prevent multiple myeloma progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3828.
Abstract 4982: The somatic mutation signature detected in gynecological mucosal melanoma
Authors: Zhongwu Li, Lianyi Shen, Siyao Liu
Journal: Cancer Research (2023)

Abstract Background: Gynecological Mucosal Melanoma(GMM) is aggressive disease with a poor prognosis, where few studies focusing on its target drug and mutation signatures. Cancer as outcome of DNA mutagenesis process and can be inferred from somatic mutations signature by analyzing the genome sequence. Due to the rapid development of next-generation sequencing (NGS) and molecularly driven targeted therapy, discovering different mutation signature in cancer plays an important role in precision medicine. Methods: The study was conducted at a high-volume melanoma center, the Peking University Cancer Hospital. We enrolled female patients with melanoma (n = 22) from 2017 to 2021. Subsequently, whole-exome sequencing performed on the Formalin-fixed paraffin-embedded (FFPE) specimens from 22 GMM patients and match normal tissues of patients. Tumor mutational burden (TMB) was measured as the number of nonsynonymous somatic mutations of whole-exome sequence coding region. Mutation signature detection base pair of six substitution subtypes: C&amp;gt;A, C&amp;gt;G, C&amp;gt;T, T&amp;gt;A, T&amp;gt;C, and T&amp;gt;G. NMF can be used to decompose matrix A into two nonnegative matrices. Results: In all mutations of 22 GMM patients, we screen two mutation signatures. Signature 1 showed a strong correlation [0.77;cosine similarity value (CSV)] to the signature 3 from the COSMIC database, which represents failure of DNA double-strand break-repair by homologous recombination, which predominated in 55%(12/22) GMM patients. Signature 2 showed a strong correlation to Cosmic signature 1 (CSV = 0.791), which is has been found in all cancer types correlated with age cancer diagnosis. Patient-18 did not any treatment in our hospital, follow-up was lost. Kaplan-Meier revealed that Signature 2 was associated with longer overall survival in GMM patients and later recurrence or progression. Conclusions: This study aimed to identify prognostic markers and the development of targeted therapy for the treatment of GMM. Citation Format: Zhongwu Li, Lianyi Shen, Siyao Liu. The somatic mutation signature detected in gynecological mucosal melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4982.